CDK9 recruits HUWE1 to degrade RARα and offers therapeutic opportunities for cutaneous T-cell lymphoma
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous non-Hodgkin lymphoma originating in the skin and invading the systemic hematopoietic system. Current treatments, including chemotherapy and monoclonal antibodies yielded limited responses with high incidence of side effects, highlighting the need for targeted therapy. Screening with small inhibitors library, herein we identify cyclin dependent kinase 9 (CDK9) as a driver of CTCL growth. Single-cell RNA-seq analysis reveals a CDK9<sup>high</sup> malignant T cell cluster with a unique actively proliferating feature. Inhibition, depletion or proteolysis targeting chimera (PROTAC)-mediated degradation of CDK9 significantly reduces CTCL cell growth in vitro and in murine models. CDK9 also promotes degradation of retinoic acid receptor α (RARα) via recruiting the E3 ligase HUWE1. Co-administration of CDK9-PROTAC (GT-02897) with all-trans retinoic acid (ATRA) leads to synergistic attenuation of tumor growth in vitro and in xenograft models, providing a potential translational treatment for complete eradication of CTCL.
Authors
- Lihong Hu (ORCID: https://orcid.org/0000-0003-3231-2829)
- Meng‐Ying Yang
- Cindy Lin (ORCID: https://orcid.org/0000-0002-9930-0411)
- Xiaobao Yang (ORCID: https://orcid.org/0000-0001-5266-7673)
- Chen‐Hui Luo (ORCID: https://orcid.org/0000-0001-6570-9342)
- Jie-Yang Liu
- Li Zhou (ORCID: https://orcid.org/0000-0001-5348-3681)
- Ying Lu (ORCID: https://orcid.org/0000-0003-4657-0810)
- Xing Qiu (ORCID: https://orcid.org/0009-0000-1382-9967)
- Xia Li (ORCID: https://orcid.org/0000-0001-7236-0855)
- Xuehong Zhang (ORCID: https://orcid.org/0000-0001-8040-4141)
- Biao Jiang (ORCID: https://orcid.org/0000-0002-3851-7115)
- Guoqiang Chen (ORCID: https://orcid.org/0000-0003-4936-2363)
- Ren-Hong Sun
Institutions
- Shanghai Jiao Tong University (CN)
- Dalian Medical University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- XinHua Hospital (CN)
- Ruijin Hospital (CN)
- ShanghaiTech University (CN)
- Ministry of Education (TH)
- Shanghai Chengtou (China) (CN)
- Hainan Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-12-04
- DOI
- https://doi.org/10.1038/s41467-024-54354-3
- Citations
- 6
- Primary Topic
- Cutaneous lymphoproliferative disorders research
- Type
- article
- Field-Weighted Citation Impact
- 3.21
Funders
- National Natural Science Foundation of China
- Science and Technology Commission of Shanghai Municipality
- National Key Research and Development Program of China